This competitive renewal of the R01 AR 32599 is aimed at discovering the etiology of endemic pemphigus foliaceus (PF), also known as Fogo Selvagem (FS). Some of the advantages that an organ-specific autoimmune disease such as FS (which is epidermal-specific) offers to research in autoimmunity are related to the fact that anti-Dsg1 (desmoglein 1) autoantibodies are pathogenic and the self-antigen, Dsg1, is fully characterized. The Amerindian reservation of Limao Verde, located in the state of Mato Grosso do Sul, Brazil, is the home of 1,351 members of the Terena tribe of Amerindians (as of September 10, 2006), and is an active focus of FS, exhibiting a ~3 percent prevalence of disease. For the last 12 years, we have systematically collected clinical and serological data from FS patients, as well as clinically normal individuals residing in and around this settlement. Anti-Dsg1 autoantibodies in healthy individuals from LV and neighboring communities are common, and directly related to proximity to this reservation. We have also observed the clinical and serological conversion from normal to disease state in 11 individuals. This transition was heralded from non-pathogenic IgG autoantibodies targeting the EC5 domain of Dsg1 during the pre-clinical stage to a pathogenic IgG response against the Dsg1 EC1-2 domains during the onset of clinically active disease. We have also reported that the pathogenic antibodies are IgG4 restricted. We have recently found that the IgM anti-Dsg1 autoantibody response is distinctive to FS patients exposed to their native rural environment, marker that is not prevalent in other forms of pemphigus. This novel autoantibody is also detected in clinically normal individuals living in LV and its neighboring rural regions since early childhood, being absent in neonates. Two prong approaches, i.e. epidemiological and immunological are utilized to explore the central hypothesis of the grant that states that an environmental antigen(s), i.e., hematophagous insect bites sensitize individuals living in Limao Verde. We believe that both approaches are not exclusive but complementary to each other. The immunological methodologies will yield new immunological assays and instruments that will facilitate the identification of individuals at risk to develop FS. For example, based on the assessment of IgG subclass anti- Dsg1 antibodies in a large set of FS and controls we have developed an "IgG4 classifier/predictor," which is highly sensitive and specific. This instrument defines a serum as having serological features of FS (pre-clinical stage) or features of a healthy individual. Using this new "IgG4 classifier/predictor" we have analyzed the sera of 96 members of 3 cohorts from Limao Verde and have identified 21 individuals with serological features of FS and 75 with features of healthy controls (samples collected in 2005). These individual at risk to develop FS will be HLA-typed and are under close surveillance for any evidence of clinical FS. Completion of the aims of this project will benefit our understanding of human autoimmune diseases seen in the USA and around the world. Narrative: The grant R01 AR32599 is aimed at disclosing the etiology of a human autoimmune skin disease, endemic pemphigus foliaceus, which is endemic in Brazil. At the completion of this application we will have a better understanding of other human autoimmune diseases like lupus erythematosus, rheumatoid arthritis, thyroiditis, and others.